FR2462439A1 - NOVEL PROCESS FOR THE PREPARATION OF PRODUCTS DERIVED FROM 7 - / (2-ARYL) 2-HYDROXYIMINO ACETAMIDO / CEPHALOSPORANIC ACID - Google Patents

Abstract

1. Process for the preparation of the products with the general formula I' : see diagramm : EP0023453,P18,F1 syn isomer in which R represents a phenyl, thienyl, furyl or thiazolyl radical, the said radicals not being substituted or being substituted by at the most two substituents chosen from the group formed by the halogens, the amino radical and the protected amino radicals, R1 represents a hydrogen atom, a protection group for the hydroxyl radical, an alkyl, alkenyl, alkynyl or a cycloalkyl radical, having at the most 6 carbon atoms, these radicals possibly being substituted, or R1 represents an acyl radical, R'2 and R3 are such that, either R'2 represents a hydrogen atom and R3 represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R3 represents a hydrogen atom and R'2 represents : - either a halogen atom, - or an alkyl, cycloalkyl, alkoxy or alkylthio radical, having at the most 5 carbon atoms, - or an acetoxymethyl or a carbamoyloxy methyl radical, - or a see diagramm : EP0023453,P18,F2 radical in which Alk is an alkyl containing from 1 to 4 carbon atoms, - or a -CH2 -S-R5 radical in which R5 represents either a heterocycle with 5 or 6 links containing from 1 to 4 hetero-atoms chosen from S, N and O and possibly substituted, or an acyl radical having from 2 to 4 carbon atoms, or a condensed heterocycle, - or an azidomethyl radical, - or a see diagramm : EP0023453,P18,F3 radical, A' represents a hydrogen atom, an equivalent of an alkali metal, an alkaline-earth, of magnesium, of ammonium or of an organic amino base, or an ester group, or the group CO2 A' represents -CO2 (cation) , n represents an integer from 0 to 2, given that when R'2 represents the see diagramm : EP0023453,P18,F4 radical, -CO2 A' represents -CO2 (cation) , which process is characterized in that a product with the formula II : see diagramm : EP0023453,P18,F5 in which R and R1 have the previous significance and A1 represents a hydrogen atom or an equivalent of alkali metal, alkaline-earth, magnesium, ammonium or an organic amino base, is treated first in a solvent and possibly in the presence of a base with a product with the formula III : R4 SO2 Hal in which R4 represents an alkyl, aryl or aralkyl radical, possibly substituted, and Hal represents a halogen atom and the resultant product is made to react in a solvent and possibly in the presence of a base on a product with the formula IV : see diagramm : EP0023453,P19,F1

Description

The present invention to the realization of which participated

  Messrs. René HEYMES, Jean JOLLY and Primo RIZZI, relates to a new process for the preparation of the products of general formula I: ## STR1 ## wherein R represents a phenyl, thienyl or furyl radical; thiazolyl, said radicals being unsubstituted or substituted at most by two substituents selected from the group consisting of halogens, the amino radical and the protected amino radicals OR1 represents a hydrogen atom, a hydroxyl radical protecting group, an alkyl radical, alkenyl, alkynyl or cycloalkyl having at most 6 carbon atoms, these radicals being optionally substituted, or R1 represents an acyl radical, R2 and R3 are such that either R2 represents a hydrogen atom and R3 represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms or R3 represents a hydrogen atom and R2 represents:

- a halogen atom, -

  or an alkyl, cycloalkyl, alkoxy or alkylthio radical having at most 5 carbon atoms, or an acetoxymethyl or carbamoyloxy methyl radical;

  or a radical -NE- -Alk in which Alk is an alkylecomponent

  from 1 to 4 carbon atoms, or a radical -CH 2 -S-R 5 in which R 5 represents or

  a 5- or 6-membered heterocyclic ring having from 1 to 4 hetero

  atoms selected from S, N and O, and optionally substituted, or R5 represents an acyl radical having 2 to 4 carbon atoms or R5 represents a fused heterocycle, - an azidomethyl radical, A represents a hydrogen atom, an equivalent of an alkali metal, alkaline earth metal, magnesium, ammonium or a

  amino organic base or an ester group.

  n represents an integer of 0 to 2> process characterized in that it is first treated in a solvent, and optionally in the presence of a base, a product of formula II: R - C02A1 he OR in which R and R1 have the above meaning and A1 represents a hydrogen atom or an equivalent of alkali metal, alkaline earth metal, magnesium, ammonium or an organic amine base, with a product of formula III: R4 SO2Hal III in which R4 represents an optionally substituted alkyl, aryl or aralkyl radical and Hal represents a halogen atom and causes the resulting product to act in a solvent and optionally in the presence of a base on a product of formula IV: (o) n

H2N S R3

R2 IV

  C02A Among the radicals that can represent R, mention may be made of

  especially the 2-furyl radical, the radicals 1,3-

  thiazol-4-yl or 2-amino-5-chloro-1,3-thiazol-4-yl and

  2-amino or 2-amino protected 1,3-thiazol

4-yl.

  The aryl radicals that R represents can be substi-

  by the halogen atoms, fluorine, chlorine, bromine or

  iodine. The preferred atom is the chlorine atom.

  The protective group by which the amino group can be protected can be chosen from the following radicals:

  an alkyl radical of 1 to 6 carbon atoms such as

  tert-butyl or tert-amyl, an acyl group

  phaetic, an aromatic or heterocyclic acyl group or a carbamoyl group, a lower alkanoyl group such as,

  for example, formyl, acetyl, propionyl, butyryl, iso-

  butyryl, valeryl, isovaleryl, oxalyl, succinyl,

  Loyle; a lower alkoxy or cycloalkoxycarbonyl group such

  that, for example, methoxycarbonyl, ethoxycarbonyl, propoxy-

  carbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, tertpentoxycarbonyl, hexyloxycarbonyl; benzoyl, toluolyl, naphthoyl, phthaloyl, mesyl, phenyl acetyl, phenylpropionyl, an arylalkoxycarbonyl group such as benzyloxycarbonyl. The acyl group may be substituted, for example, with chlorine, bromine, iodine or fluorine. Such a group

  can be, for example, a chloroacetyl, dichloroacetyl,

  acetyl, trichloroacetyl, trifluoroacetyl or bromoacetyl.

  The protective group of the amino radical may also be a lower aralkyl group such as benzyl, 4-methoxy

  benzyl or phenylethyl, trityl, 3,4-dimethoxybenzyl, benzyl

  dryle, a haloalkyl group such as trichloroethyl; a chlorobenzoyl, paranitrobenzoyl, para-tert-butylbenzoyl, phenoxyacetyl, caprylyl, n-decanoyl, acryloyl group,

  a methylcarbamoyl, phenylcarbamoyl, naphthyl-

  carbamoyl and the corresponding thiocarbamoyls.

  The above list is not an exhaustive list.

  It is obvious that other groups protecting the

  amines, groups known in particular in the chemistry of pep-

  tides can also be used.

  The protective group of the hydroxyl radical that may represent R 1 may be chosen from the following list: R 1 may represent an acyl group such as, for example,

  formyl, acetyl, chloroacetyl, bromoacetyl, dichloro-

  acetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl,

  phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl.

  Mention may also be made of ethoxycarbonyl groups, metho-

  xycarbonyl, propoxycarbonyl, benzyloxycarbonyl, tert-butoxy-

  carbonyl, 1-cyclopropylethoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyranyl, trityl,

  benzyl, 4-methoxybenzyl, benzhydryl, trichloroethyl, 1-

  methyl 1-methoxyethyl, phthaloyl.

  Other acyls such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl and succinyl may also be mentioned.

and pivaloyl.

  Mention may also be made of phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl and para-nitrobenzoyl radicals.

  para-tert-butylbenzoyl, caprylyl, acryloyl, methylcarba-

  medium, phenylcarbamoyl, naphthylcarbamoyl.

  Other values of R 1 include, for example, methyl, ethyl, propyl, isopropyl, butyl,

  sec-butyl, tert-butyl, pentyl, hexyl, vinyl, allyl,

  pargenyl, ethynyl, butenyl, cyclopropyl, cyclobutyl, cyclohexyl,

pentyl, cyclohexyl.

  Among the groups by which the alkyl, alkenyl, alkynyl and cycloalkyl radicals represented by R 1 may be substituted, mention may be made of: alkoxycarbonyl groups such as ethoxycarbonyl or tertbutoxycarbonyl, carboxy, salified carboxy, nitrile, amino or alkyl or dialkylamino groups,

  aryl-groups such as phenyl, tetrazolyl, thiazol

  optionally substituted lyle such as 4-methyl or 4-amino thiazol-2-yl, pyridinyl,

  azido or arylthio groups such as phenyl

  substituted-thio, - hydroxyl groups, halogen such as chloro, bromo,

  iodo, fluorocuR1 may represent, for example, the radical 2-

  bromo propen-2-ylep - acyl groups such as alkanoyl or arbamoyl optionally substituted, the alkyloxy or alkylthio groups,

  the groups isoureido, thiocyanato, aminohydrazino, methylthio.

  Among the other values of R 1, in particular the acyl value, mention may be made, in addition to the radicals indicated above, of the aroyl ester radicals such as optionally substituted benzoyl, optionally substituted carbamoyl aminoalkanoyl or amino

substituted alkanoyl.

  The substituent R at position 2 of the cephem ring is in the 0 configuration. R3 can represent a methyl radical,

  ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl.

  For the values of R 2, mention may be made of methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy and ethoxy radicals. , propoxy, butoxy,

  isopropyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, iso-

  pentyloxy, tert-pentyloxy, neopentyloxy, methylthio, ethyl-

  thio, propylthio, butylthio, isopropylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, tert-pentylthio, neopentylthio. The values acetamido, propionyl may also be mentioned.

  amido, butyrylamido, isobutyrylamido.

  Among the preferred values of R5, mention may be made of

  acetyl radicals, 1-methyltetrazolyl, 2-methyl-1,3,4-

  thiadiazolyl, 3-methyl 1,2,4-thiadiazol-5-yl, 3-methoxy

  1,294-thiadiazolyl, 1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-

  thiadiazol-5-yl, 3-hydroxycarbonylmethyl 1,2,4-thiadiazole

  -yl, 5-methoxy-1,2,4-thiadiazol-3-yl, 4-methyl-5-hydroxy-

  carbonylmethyl, 1,3-thiazol-2-yl, 1-dimethylaminoethyl 1,2,3,4-

  tetrazol-5-yl, 13.3,4-triazol-5-yl, 2- (thien-2-yl) 1H-1,3,4-

  triazol-5-yl, 1-amino-2-trifluoromethyl-1,3,4-triazol-5-yl,

  4-hydroxycarbonylmethyl-1,3-thiazol-2-yl

  Among the values of A, there may be mentioned, for example, a

  equivalent of sodium, potassium, calcium, magnesium, diethyl

  amine, trimethylamine, triethylamine, methylamine, propylamine,

  N, N-dimethylethanolamine, ethanolamine.

  Among the values of A representing an ester group,

  for example, butyl, isobutyl, tert-

  butyl, pentyl, hexyl, benzhydryl, p-methoxybenzyl, 3,4-

  dimethoxybenzyl, acetoxymethyl, pivaloyloxymethyl.

  The action of the product of formula III on the product of

  Formula II is preferably carried out in an anhydrous solvent.

  It is possible, for example, to operate in acetone, dimethyl

  formamide, ethyl acetate, tetrahydrofuran, acetoin

  nitrile, carbon tetrachloride, chloroform, chlo-

  methylene chloride, toluene, xylene, ethyl ether,

  isopropyl ether, N-methyl pyrrolidone or dimethyl-

  acetamide. When the product of formula II which is employed is in free acid form, that is to say when A1 represents a hydrogen atom, the action of the sulfonyl halide of formula

  III is preferably carried out in the presence of a base.

  This base may be chosen from the following list: triethylamine, N, N-dimethylaniline, tributylamine, N-methyl morpholine, pyridine, picoline or carbonate or sodium or potassium acid carbonate,

  The preferred base is triethylamine.

  When the product of formula II is a salt, that is to say when the substituent A1 represents an equivalent of alkali metal, alkaline earth metal, magnesium, ammonium or an organic amine base, the action of the halide of formula III

  can be performed in the absence of base.

  The sulfonyl halide that III can represent

  preferably tosyl chloride.

  However, other sulfonyl chlorides can be used

  such as methane sulphonyl chloride.

  The formation reaction of the reactive derivative of the product of formula II by the action of the product of formula III can be

  performed at room temperature or while cooling.

  In particular, when R represents a group comprising

  as an unprotected amino group, it is advantageous to

  to kill the formation reaction of the reactive derivative of the product II while cooling. A temperature of about -250C to 0 C

is then preferred.

  The reactive derivative of the product of formula II which is formed during the first step of the present process appears to be the anhydrous carboxylic-sulfonic mixture of formula:

R - - COOS02-R4

  OR1 In one of the embodiments of the invention, such a

  mixed anhydride has to be isolated in the crystallized state and

  ized. The second part of the process consists in acylating 7-amino cephalosporanic acid or a derivative thereof (product of

formula IV).

  The reaction is preferably carried out by adding the solution of the reactive derivative of product II in a solution of

product IV.

  When A does not represent an equivalent of salt, the disso-

  the product IV is operated in the presence of a base,

preferably triethylamine.

  The solvent in which the product of formula IV is dissolved

  is preferably methylene chloride, but other sol-

  can be used, since the solvent is not critical

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for the present reaction.

  The present reaction can advantageously be carried out at low temperature. It may be preferable to adopt a

temperature from -750C to + 5C

  Naturally, depending on the values of the substituents A, R or R1, the steps of the present process can be followed if necessary, by steps of purification or cleavage of the

  or protecting groups. The processes of such purifications

  cations or cleavages are known in literature.

  The steps of this process can be followed by the

  salification or esterification of the products obtained.

  In Belgian Patent No. 850,662, the Applicant Company has described a process for the acylation of 7-ACA using, for the preparation of synt products, the symmetrical anhydride formed in

  presence of dicyclohexylcarbodiimide.

  The present method has the advantage of requiring only one

  single equivalent of 2-aryl-2-oxyiminoacetic acid.

  French Pat. No. 2,348,219 describes examples of acylation of 7-ACA by reactive derivatives of the acid.

  2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetic acid formed in

  of dimethylformamide and phosphorus oxychloride.

  However, it is stated in the examples of the patent that the product obtained after the reaction must be purified by

column chromatography.

  The present process has the advantage of direct driving

  to a pure final product with excellent results.

  is lying. The invention more particularly relates to a process for the preparation of the products of formula IA: (0), 1 * A s C OHS A

O H2-R'2

! ) 2H

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syn isomer

  wherein R 'represents a hydrogen atom or a group

  protecting the amino group, R'1 represents a group

  protecting the hydroxyl group or an alkyl, alkenyl or alkynyl radical having not more than 4 carbon atoms

  R'2 represents an acetoxy, 1-methyl 1 (H) tetrazol-

  -ylthio, 2-methyl-1,3,4-thiadiazolylthio or azido, nil represents 0 or 1

  corresponding to a product of formula I in which R represents

  a 2-amino-1,3-thiazol-4-yl or 2-amino-protected 1,3-thiazol-4-yl radical, R1 has the values of R'1, A represents a hydrogen atom,

  R2 represents: CH2-Rt2 in which R'2 has the above values;

dentes and n has the values of ntp

  characterized in that one treats first in a sol-

  and optionally in the presence of a base, a product of formula IIA

At NHR,

- C0.0 IIA

  in which R 'and R'1 have the above meaning and A1 represents a hydrogen atom or an equivalent of alkali metal, alkaline earth metal, magnesium, ammonium or an organic amine base, by tosyl chloride and causing the resulting product to act in a solvent and in the presence of a base on a product of formula IVa) H2N S + CH2_R'2 IVa

C

01H2-Rt2 lIVa C02H

  in which R'2 and n 'have the preceding meaning.

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  The invention relates more particularly to the process as defined above and characterized in that the solvent in which the product of formula III is reacted with the product of formula II or tosyl chloride on the product of formula IIA is chosen. in the group formed by acetone,

  dimethylacetamide, ethyl acetate, tetrahydrofuran

  acetonitrile, carbon tetrachloride, methylene chloride, toluene, dioxane, isopropyl ether, N-methyl pyrrolidone and dimethylformamide, and more particularly in that the solvent in which the product of Formula III on the product of formula II or tosyl chloride on the product of formula IIA is dimethylacetamide. The invention more particularly relates to a process, characterized in that the solvent in which is effected on the product of formula IV or IVa respectively the product resulting from the action of the product of formula III on the product of formula II or the product resulting from the action of tosyl chloride on the product of formula IIA is methylene chloride and in that the base in the presence of which it is optionally carried out during the various phases of the

process is triethylamine.

  The invention is especially directed to the process characterized in that the action of the product of formula III on the product of formula II or the action of tosyl chloride on the product of formula IIA as well as the action of the products resulting from these operations. on products of formula IV

  or IVa are performed at low temperature.

  The invention particularly relates to a method of

  preparation of 3-acetoxymethyl 7- / 2- (2-amino-4-

  thiazolyl) 2-methoxyimino acetamido / ceph-3-th-4-carboxylic acid isomer, characterized in that tosyl chloride is reacted at low temperature in dimethylacetamide and in the presence of triethylamine. - (2-amino-4-thiazolyl) -2-methoxyiminoacetic acid, isomer syn and made

  act in methylene chloride and in the presence of triethyl

  amine, the resulting product on 7-amino cephalosporin

  ranique. Finally, the invention relates more particularly to a

  process for preparing 3-acetoxymethyl 7- / 2- (2-

  tritylamino-4-thiazolyl) 2-methoxyiminoacetamido / ceph-3-th -carboxylic acid isomer, characterized in that tosyl chloride is reacted at low temperature in dimethylacetamide and in the presence of triethylamine. - (2-Tritylamino 4-thiazolyl) 2-methoxyiminoacetic isomer syn and act in methylene chloride and in the presence of triethylamine the resulting product on the acid

7-amino cephalosporanic acid.

  The products of formula II in which R represents a

  phenyl, thienyl or furyl radical are described in

  bind in French Patent 2,137,899.

  The products of formula II in which R represents a thiazolyl amino or thiazolyl protected amino radical are

  described in Belgian Patent 850,662.

  The products of formula II in which R represents a thiazolyl radical can be prepared starting from products of formula: CHE3-g-CO2Alk The method used is identical to that described in French Patent 2,383,187, thiourea being replaced by thioformamide . The products obtained before saponification, are then subjected to the action of a product of formula s H2N-OR1

then saponified.

  The products of formula II in which R represents a thiazolyl radical substituted with an amino radical and a halogen radical may be prepared, for example, by the action of a halogenation reagent on the product of formula II

  in which R represents a thiazolyl amine radical.

  The products of formula IV are described in the literature. In particular, the products in which n represents the

  number 1 or 2, are described, for example, in the French patent

but 2,387,234.

  The method, object of the invention, makes it possible to obtain

  products that are cephalosporins with

  properties well known as antibiotic drugs.

  In addition, the products described in the examples, the following products constitute in particular substances that can be obtained by the process of the invention: - 7 - [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl acid; amino / 3 - [(1-methyltetrazol-5-yl) thiomethyl] ceph-3-th -carboxylic acid, syn isomer, its salts with alkali metals, alkaline earth metals, magnesium, ammonia, organic amine bases and its esters with easily cleavable groups, - 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl] amino-ceph-3-th-4-carboxylic acid syn isomer, its salts with alkali metals, alkaline earths * magnesium, ammonia, organic amine bases and its esters with easily cleavable groups,

  7 - (2-yl) -2-yl) -2-methoxyiminoacetyl / amino / 3- acid

  carbamoyloxymethyl ceph-3-th 4-carboxylic syn isomer, its salts with alkali metals, alkaline earth metals, magnesium, ammonia, aminated organic bases and its

  esters with easily cleavable groups.

  The following examples illustrate the invention without however

limit it.

  Example 1: 3-Acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido] ceph-3-th-4-carboxylic acid syn isomer Step A * AnhXdride para-toluene sulfonyl-2-2 2-tritylamino 4-thiazolyl ) 2methoxyiminoacetic *

  59.92 g of the triethylamine sol of 2- (2-

  tritylamino 4-thiazolyl) 2-methoxyimino acetic acid, 500 cc of

  ketone and 20.97 g of para-toluenesulfonyl chloride.

  Stir one hour at room temperature and then 15 minutes in

  a bath of ice water. It is wrung and rinsed with acetone.

  After drying, 12.1 g of insoluble product are obtained.

  The filtrate containing the expected product is maintained in a

  ice water bath until use.

  Analysis on a fraction of dry extract: NMR (cncI3) ppm 2.39: HJ 9 Hz 4.15 = N-OCH3 J = 4 Hz 6.74 proton in 5 thiazole J = 5.5 Hz 7.3 grouping Trityle, Infra-Red in CHC13

3 _1

  -C = 0 1821, 1782, 1760, 1715 cm 'Ultra-Violet a) In ethanol Inflexion Inflection Inflection Inflection Inflection Inflexion b) Solution c Inflection Inflection Maximum Inflexion The salt of: 227 nm = 26 200: 237 nm t = 100: 260 nm = 12 6oo00: 267 nm 272 nm: 295 nm E = 5.400 decinormal chlorohydric acid in ethanol

  ______________ ___ 2--2-2-2-2 ---- 2-22-2 -____

  : 227 nm = 23,500: 265 nm: 275 n-m - = 12,900

288 nm.

  triethylamine of 2- (2-tritylamino) 4-

  thiazolyl) 2-methoxyiminoacetic acid was obtained as follows: 44.3 g of 2- (2-tritylamino-4-thiazolyl) acid were mixed

  2-methoxyiminoacetic acid, 250 cm3 of acetone and 15 cm3 of triethyl

  amine. We observe a dissolution then a crystallization. It is stirred for 10 minutes in an ice-water bath, drained, washed with

  acetone and then with ether. 46.4 g of salt are obtained after drying.

ge.

  Stage B s Acid 3-Acetyl 7: J _-- o 4-

  thiazolyl) 2-methoxyiminoacetamido / ceph-3-th 4-carboxylic acid

syn isomer

  Approximately 30 minutes after completion of Stage A above

  27.2 g of 7-amino cephalosporanic acid, cm 3 of a molar solution of sodium hydrogen carbonate are mixed

  and 100 cm3 of water. Stirred 30 minutes at room temperature.

  The product is then completely dissolved (pH 7.2). Cm 3 of acetone is added and the mixture is cooled to +5 ° C.

  ice-methanol bath. In 15 minutes, the solution is introduced

  ice cream prepared in stage A by maintaining the temperature

inside at +50 0.

  We observe a precipitation and a redissolution.

  50 cm3 of a molar solution of sodium carbonate are added.

sodium. The pH is then 7.85.

  Let it warm for one hour 30 minutes.

  The acetone is then removed under reduced pressure at approximately 30 ° C. 100 cm3 of water and then 20 cm3 of formic acid are added

* 66%.

  The mixture is stirred for 15 minutes at room temperature, filtered, washed 3 times under vacuum and gives 97.2 g of crude product.

  The product is taken up in 120 cm3 of acetone.

  The mixture is stirred for one hour at room temperature and then for 30 minutes in an ice-water bath. It is filtered off, rinsed twice with acetone-ether (21) and then with ether. Vacuum dry

  at 400C. 48.72 g of purified product are thus obtained.

  Example 2: 3 - [(2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl] acid

  7- / 2- (2-Tritylamino-4-thiazolyl) -2-methoxyiminoacetamido / ceph-

3-th 4-carboxylic syn isomer

  3.44 g of 3 - / (2-methyl-1,3,4-thiadiazole-5-

  yl) thiomethyl / 7-amino cephalosporanic in 10 cm3 of distilled water

  and 22 cm3 of a molar solution of bicarbonate of

  sodium. Stir one hour at room temperature. An insolu-

  ble persists. 15 cm3 of acetone is added and then cooled to

  + 50C inside by a methanol-ice bath.

  The solution prepared simul-

  p-toluenesulphonic anhydride-2- (2-tritylamino-4-thiazolyl) -methoxyiminoacetic acid isomer syn

  in Step A of Example 1 on a quantity ten times less.

  It is left to spontaneous warming for one hour 30 minutes. It is wrung, rinsed with water and acetone a slight insoluble. 2 cm3 of acetic acid is added to the filtrate. We try to

  again, we rinse with acetone a new insoluble.

  Acetone is removed under reduced pressure in a water bath at 30 ° C. Precipitation is observed. 10 cm3 of water and then 1.3 cm3 of formic acid are added. Stir 15 minutes at room temperature, drain, rinse 3 times with water. Dry overnight under vacuum.

7.895 g of crude product are obtained.

  Example 3: 3-Azidomethyl 7- / 2- (2-tritvlaminothiazol-4-)

  yl) 2 - [(1-methyl-1-methoxyethoxy) imino] -acetamido] -phi-3-th -carboxylic acid syn-isocyanate R-α-Antrimethylenesulfon-2- (2-triamino-4-thiazolyl) -2- Methyl 1-methoxyethoxy) imino acetic isomer sxn

  6.63 g of triethylamine salt of 2- (2-

  tritylamino 4-thiazolyl) 2- / 1-methyl-1-methoxyethoxy

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  imino / acetic acid syn isomer, 60 cm3 of acetone and 2.19 g of para-toluene sulfonyl chloride. The mixture is stirred for one hour at room temperature and then for 15 minutes in an ice bath. It is wrung and rinsed with acetone. After drying, 1.16 g of triethylamine hydrochloride are obtained. the filtrate is stored in

  an ice bath until use.

  Stage B: 3-azidomethyl 7- / 2- (2-tritylamino-thiazol-4-)

  yZI2-LQ1-methyl-1-methoxethoxy) imino / acetamido / ceph-3-th

  _ __ _______ ____ _ ______ - ____ -___ _____ -__ -_______

4-carboxic syn isomer

  2.55 g of 3-azidomethyl-7-amino-ceph-3-yl 4-carboxylic acid, 10 cm 3 of distilled water, 22.5 cm 3 of solution are mixed.

  molar, sodium hydrogen carbonate and then 10 cm3 of acetone.

  Stirred 10 minutes at room temperature. The mixture is cooled to + 50 ° C. with a methanol-ice bath, and the solution prepared in Stage A is introduced at this temperature for 10 minutes at this temperature. The mixture is stirred for two hours with spontaneous warming. The acetone is removed under reduced pressure in a

  water bath at 30 C and then acidified with 1 cm3 of formic acid.

  The insoluble material is filtered off and rinsed twice with water.

  The insoluble matter is taken up in ethyl acetate and stirred for 15 minutes at room temperature. The initial acid is filtered off and rinsed with ethyl acetate. After drying, 0.36 g of starting acid is recovered. The filtrate is dried, the solvent is evaporated and

gets a resin. Rf .: 0.5 (Ethyl acetate - ethanol - water: 70 - 20 - 10).

  2- (2-Tritylamino-4-thiazolyl) 2 - [(1-methyl) -1-

  methoxy ethoxy) imino / acetic isomer sn is described in the

Belgian patent 865,298.

  The triethylamine salt of this acid, salt used starting from Stage A of Example 3, was prepared as follows: 5.01 g of 2- (2-tritylamino-4-thiazolyl) -2- (1-methyl) acid was mixed 1-methoxyethoxy) imino / acetic isomer syn

  cm 3 of methylene chloride and 1.5 cm 3 of triethylamine.

  The solvent is evaporated under reduced pressure in a water bath at 30-350C. The residue is taken up in ethyl ether. Disintegrate, drained, rinsed with ether, dried at 400C under pressure

  scaled down. 5.62 g of expected salt are obtained.

  EXAMPLE 4 3-Azidomethyl 7- / 2- (2-Tritylamino Thiazol-4-Acid)

  yl) 2 - ((1-methyl-1-methoxyethoxy) imino / acetamido / ceph-3-th

4-carboxylic syn isomer

  Stad To: 6QDyti! JReE = IúJènesuif onique 2-j2 -trityl -

  ---- u ----- - - - - ---------- - ---- ------- ------------- - -

  amino-4-thiazolyl = 2-L-1-methyl-1-methoxy-ethoxy-zimino acetic acid isomer 6.03 g of triethylamine salt of 2- (2-tritylamino-4-thiazolyl) -2- (1-methyl-1) -methoxy ethoxy) imino / acetic acid and 2.28 g of para-toluenesulphonyl chloride in 30 cm3 of anhydrous acetone. A few crystalline product primers are added to an acetone ether mixture (1-1) to

  from the product obtained in Stage A of Example 3.

  Agitate an hour 30 minutes to 2000. We obtain a mass

  thick. 30 cm3 of sulfuric ether are added at 200 ° C.

  Stir five minutes at 200C to homogenize and wring the

  The product is rinsed with 3 times 10 cm 3 of sulfuric ether.

  America. It is dried under vacuum at 200C. 6.54 g of product are obtained

  composed of the desired anhydride and triethylhydrochloride

  amine. The mother liquors are concentrated to dryness and taken up in cm 3 of ether. This recovers a second jet of 1 g. The pure anhydride free of triethylamine hydrochloride was obtained as follows: The two previous jets (7.54 g) were dissolved in 60 cm3 of methylene chloride. The solution is washed twice with 30 ml of distilled water. It is dried, drained, rinsed and brought to dryness under vacuum without exceeding 300 ° C., and 6.5 g of resin are obtained. This residue is taken up in 20 cm3 of sulfuric ether, stirred at 200 ° C., a complete dissolution followed by crystallization is observed. It is filtered at 2000, rinsed with 3 times 10 cm3 of ether and dried under vacuum at 200C. 5.5 g of expected product are obtained. Ultraviolet Spectrum a) In ethanol Inflexion 222 nm E1 = 562 E = 36 900 227 nm E1 = 505-234 nm E1 = 403 = 26400 * 1 "260 nm E = 183 = 1,200 265 nm E 163 271 nm E1 = 141

300 nm E I = 69 E = 4500.

  b) Decinormal solution o Hydrochloric acid in ethanol 4oInflexion 223 nm E 564

162462439

  Inflection 228 nm E1 = 454 264nm EB = 180 "269 nm E1 = 193 Maximum 274 nm E = 95 = 12,800 Inflection 286 nm = 176. RM ,, (CDCl3) ppm ppm 1, 45: = N-O-C11

CH3 - CH

3.2: = N-O-C - CH3

OCH3 6.55: proton at 5 thiazole,

7.28: proton of trityl.

  Stage B: 3-azidomethyl 7- / 2- (2-tritxamino-thiazol-4-)

  X122-: l-met-1-yl: 1methanol and hexamethoxy ketamido / ceph-3-th 4 carboxylic syn isomer

  0.255 g of 3-azidomethyl-7-amido-ceph-3- acid is dissolved.

  4-carboxylic acid in 2.6 cc of methylene chloride and

0.28 cc of triethylamine.

  Cool to -10 C and add in fractions in 8 minutes

  0.656 g of the mixed anhydride free of triethylhydrochloride

  amine prepared in Stage A. After 30 minutes at -10 ° C., chromatography on

  thin layer, the disappearance of the spot corresponding to 3- acid

  azidomethyl ceph-3-th 4-carboxylic acid. Two drops of acetic acid are added, washed with water and then with hydrochloric acid diluted with water, dried, evaporated to dryness and triturated in isopropyl ether. It is drained, dried and obtains 0.691 g of product

  identical to that obtained in Stage B of Example 3.

  Example 5: 3-Acetoxymethyl-7- [2- (2-tritylamino) -thia] acid

  zolvl) 2-methoxy-imino acetamido / ceph-3-th 4-carboxylic acid isomer syn A) 247.8 g of tosyl chloride are dissolved in 780 cm 3 of dimethylformamide,

  This solution is cooled to 0 ° C. and introduced at this temperature.

  576.5 g of 2- (2-tritylamino-4-thiazolyl) -2-methoxy-

imino acetic isomer syn.

  196 cm3 of triethylamine are then introduced.

  This solution is maintained at 0 ° C. and then introduced into a solution maintained at -70 ° -75 ° C. and consisting of 272 g of 7-amino cephalosporanic acid in 3 liters of methylene chloride and 450.7 cm 3 of triethylamine. Leave it for about 30 minutes at -70 ° C then add 270 cm3

  of acetic acid and then 540 cm3 of demineralised water.

  Allowed to return to -15e, -20 C and precipitates the reaction medium in 11 liters of demineralized water. We bring back

  at pH 1 - 1.2 by addition of half diluted hydrochloric acid.

  After decanting, the chioromethylenic solution is washed with 3 times 2700 cm.sup.3 of demineralized water and then the chloromethylenic solution is concentrated under vacuum at a water bath temperature of between 8 and 30 ° C. until a solution is obtained. B) The same reaction has been carried out repeated formamide used starting from the amount of ethyl acetate, C) dimethylformamide then acetone, D) dimethylformamide then tetrahydrofuran, E) dimethylformamide then nitrile, F) dimethylformamide then carbon tetrachloride , G) dimethylformamide is then methylene chloride, H) dimethylformamide is then toluene, I) dimethylformamide is then J) dimethylformamide is then isopropyl ether, K) dimethylformamide is N-methyl pyrrolydone, L) dimethylformamide has finally

methyl acetamide.

a volume of about 1350 cm3.

the expected product.

  by replacing the dimethyl reaction with the same summer replaced by summer replaced by

been replaced by aceto

  replaced by summer replaced by summer replaced by summer replaced by summer replaced by dioxane, replaced by summer

replaced by di-

  EXAMPLE 6 3-Acetomethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-thiocarboxylic acid isomer syn

182462439

  227.5 g of tosyl chloride in 750 cm3 are introduced within 2 to 3 minutes with stirring and in a nitrogen atmosphere.

of dimethylacetamide at 20 C.

  The solution is cooled to 0 ± 2 with stirring and in a nitrogen atmosphere and then introduced in rain in 10 to 15 minutes.

  and maintaining between 0 and + 20C, 595 g of 2- (2-trityl)

  amnino 4-thiazolyl) 2-methoxyiminoacetic isomer syn.

  It is maintained under stirring and nitrogen atmosphere at 0 + 2 C

  until completely dissolved or for about 15 minutes.

  We obtain a solution in which we introduce

  at 25 minutes while maintaining at O + 2 C, 166 cm3 of triethyl-

  amine. This solution maintained at .0000 * introduced imnédiatement

  in a solution maintained at -70 C of 7-amino cephalosporinic acid

  Poranic prepared extemporaneously as follows: 2.5 liters of methylene chloride are brought to the temperature of -15.18 ° C. by injection of liquid nitrogen and nitrogen gas, and then introduced in 3 to 4 minutes 250 g of acid. 7-amino cephalosporanic acid. Then add by holding

  temperature at -15 C, 383 cm3 of triethylamine.

  After complete dissolution of the 7-amino cephalosporanic acid

  that is cooled to -70, -750C by injection of liquid nitrogen.

  The introduction of the dimethyl acetamide solution is complete, the flask and the introduction system are rinsed with twice 50 cm 3 of methylene chloride and the reaction mixture is maintained at -70 ° to 750 ° C. with stirring for 30 minutes and then introduced while maintaining at -70 ° -750 ° C., the solution consisting of 250 cm3 of acetic acid and 125 cm3 of methylene chloride. Stirring is carried out at -70 ° C. to -75 ° C. and then, adding the temperature at -600 ° C., 500 cm3 of demineralized water at 0 ° C. to 50 ° C. It is kept under stirring and nitrogen and then heated to bring to 12,

  15 ° C. and poured, with stirring, into 10 liters of demineralized water.

realized at 18-200C0.

  An emulsification is obtained in which a solution of 375 cm.sup.3 of hydrochloric acid is introduced with stirring.

and 375 cc of water.

  The two phases are allowed to settle and separate and then reextracted

  with 250 cm3 of methylene chloride.

  The chloromethylenic solution is washed with deionized water (3 × 2500 cm 3) and then concentrated under vacuum (bath temperature of less than or equal to 30 ° C.) until

a volume of 1250 cm3.

  A syrupy solution of 3-acetoxymethyl 7- [2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido] acid is obtained.

  ceph-3-th 4-carboxylic isomer syn.

  To this syrupy solution is added a solution at 18-20 ° C. of 300 cm 3 of demineralized water and 1200 cm 3 of formic acid at 98. A solution is obtained which is stirred at 30 ° -35 ° C. under vacuum.

for two hours 30 minutes.

  Crystallization of triphenylcarbinol occurs, cooled to 1820 ° C., filtered, washed by mashing with a mixture of 625 cm 3 of demineralized water and 312 cm 3 of acid.

formic.

  292.5 g of triphenyl carbinol are obtained.

  Formic solution is poured in 1 minute in 10 liters

demineralized water at 18-20 ° C.

  The mixture is stirred at 15 ° C. and then 2500 g of ammonium sulphate are added, the mixture is stirred for 15 minutes and then 1250 g of ammonium sulphate are added again. The mixture is stirred for one hour at 15-20 ° C., filtered, washed with 3 times 625 cm.sup.3 of demineralized water at 0% of formic acid at 0.degree. C., and the formate is dried under vacuum at 20.degree.

expected acid.

  The formate is introduced in rain in 2080 cm3 of pure ethyl alcohol. It is heated to 50-55 ° C., maintained at this temperature for 30 minutes, cooled to 18-20 ° C. and stirred for one hour.

at this temperature.

  We squeeze, wash with 2 times 415 cm3 of ethyl alcohol

  pure, dries and gets the expected product.

  EXAMPLE 7 Acid 3-acetoxymethyl 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] ceph-3-th -4-carboxylic acid isomer The procedure is as described above in Example 6. The only The following difference was made to the procedure: A / The 7-amino cephalosporanic acid solution prepared extemporaneously is introduced after being cooled to -400C (instead of -700C), B / 7-amino cephalosporanic acid solution was prepared using 5 liters of methylene chloride and was

  introduced after cooling to -400C0.

  C / The 7-amino cephalosporanic acid solution was prepared using 250 cm 3 of triethylamine and was introduced after cooling to -400C. D / The 7-amino cephalosporanic acid solution has been prepared

  using 3.7 liters of methylene chloride and 250 cm3.

  of triethylamine and was introduced after cooling

at -400C.

  E / The 7-amino cephalosporanic acid solution was prepared using 5 liters of methylene chloride and 250 cm 3 of triethylamine and was introduced after cooling.

at -40oc.

  F / The solution of 7-amino cephalosporanic acid prepared extemporaneously is introduced after having been cooled to

-20 C.

  G / The 7-amino cephalosporanic acid solution has been prepared

  using 5 liters of methylene chloride and was introduced

  after cooling to -20 ° C.

  H / The solution of 7-amino cephalosporanic acid was prepared using 250 cm 3 of triethylamine and was introduced after

cooling to -200C.

  The 7-amino cephalosporanic acid solution was prepared using 5 liters of methylene chloride and 250 cm 3 of triethylamine and was introduced after cooling to room temperature.

-20 C.

  EXAMPLE 8 Acid 3-acetoxymethyl 7- [2- (2-amino-4-thiazolyl) -2-methoxviniminoacetamido] ceph-3-th -4-carboxylic isomer syn

  With stirring and dry nitrogen, 192 g of 2-

  Syn isomer (2-amino-4-thiazolyl) 2-methoxyiminoacetic acid in 600 cm3 dry dimethyl acetamide maintained at 20-25 ° C, stirred

after addition.

  Then, introducing the same temperature,

133 cm3 of triethylamine.

  When the introduction is complete, the reaction mixture is maintained at 20-25 ° C., then cooled to -15.degree.-100.degree. C., and then introduced slowly, keeping the solution at -15.degree.-17.degree. The following anhydrous solution: 182.5 g of tosyl chloride in

cm3 of dimethylacetamide.

  A yellow suspension is obtained which is brought to -18.degree. C., maintained at this temperature under stirring with nitrogen for one hour and then slowly introduced at this temperature.

  suspension in a solution maintained between -70 and -750C of

  7-amino cephalosporanic acid prepared extemporaneously as follows: in 2 liters of methylene chloride cooled to -150,

  -18 ° C, 200 g of 7-amino cephalosporanic acid is added.

  Then add the temperature to -15, -180C,

307 cm3 of triethylamine.

  After complete dissolution of the 7-amino cephalosporanic acid

  that the solution is cooled between -70 and -75 C.

  Rinse after introduction of the dimethyl

  acetamide, the introduction system with 100 cm3 of chloride

of methylene at -20-250C.

  The mixture is maintained between -70 and -75 ° C. with stirring and with nitrogen, and then, under the same conditions, a solution is introduced.

  200 cm3 of acetic acid in 100 cm3 of methyl chloride

  lene. Stirred at -70.degree. C., then introduced, allowing the temperature to rise to -500.degree. C., 400 cm.sup.3 of demineralized water.

at 0o + 5c.

  The mixture is heated to 50.degree. C. and a solution composed of 400 cm.sup.3 of formic acid and 400 cm.sup.3 of demineralized water is added and 1 g of 3-acetoxymethyl-2- (2-amino-4- thiazolyl) 2-methoxyiminoacetamido / ceph-3-th

  4-carboxylic syn isomer obtained previously.

  The temperature is allowed to rise to 15-20 ° C. Vacuum and distil the methylene chloride while

  introducing 2200 cm3 of demineralized water.

  After the distillation of methylene chloride,

  under vacuum and with stirring between 18 and 20 C for 30 minutes.

  then return to normal pressure, cool to 0 to + 50 ° C, stir at this temperature, wring out, then wash with two times 400 cm3 of water

  at 5% formic acid at a temperature of 0 + 50C.

  Dry at 25-30 ° C and obtain the acid formate 3-

  acetoxymethyl 7- [2- (2-amino-4-thiazolyl) -2-methoxyimino]

  acetamido / ceph-3-th 4-carboxylic syn isomer

  The formate is sieved and then introduced in rain in 1725 cm3 of ethyl alcohol at 100, at 20-25 C.

  -550C and maintains there for 30 minutes with stirring.

  It is cooled to 18-20 ° C. and stirred at this temperature for one hour. We drain, wash with twice 345 cm3 of ethyl alcohol

  100%, dry under vacuum and obtain the expected product.

  EXAMPLE 9 Acid 3-acetoxymethyl 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] ceph-3-th-4-carboxylic acid isomer The procedure is carried out according to the conditions indicated above in Example 89 the only difference following has been made to the operating mode:

  After addition of triethylamine to 2- (2-amino-4-

  thiazolyl) 2-methoxyiminoacetic isomer synt, the mixture is cooled to 0 ° C. Then the diluted tosyl chloride is introduced.

  in dimethylacetamide in 15 to 20 minutes.

  The amidification reaction carried out by addition of

  7-amino cephalosporanic acid to the mixture prepared as above.

  above is then performed in 30 minutes.

  EXAMPLE 10 Acid 3-acetoxymethyl 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] ceph-3-th -4-carboxylic isomer syn

  We operate according to the conditions indicated above in the example

  8. The only difference was made in the procedure: A / The solution of 7-amino cephalosporanic acid prepared extemporaneously is introduced after having been cooled to room temperature.

-200C.

  B / The 7-amino cephalosporanic acid solution has been prepared

  using 4 liters of methylene chloride and was introduced

  duit after cooling to -20 C.

  C / The 7-amino cephalosporanic acid solution was prepared using 204 cm3 of triethylamine and was introduced after

cooling to -20 C.

  D / The solution of 7-amino cephalosporanic acid was prepared using 4 liters of methylene chloride and 204 cm3 of

  triethylamine and was introduced after cooling to -20 C.

Claims (9)

  1 / Process for the Preparation of the Products of the Formula I: 9) n R-1CONHi R3 XOR1 0 NX \ OR O   02A syn isomer wherein R is phenyl, thienyl, furyl   or thiazolyl, said radicals being unsubstituted or   at most two substituents selected from the group consisting of halogens, amino and protected amino groups, R1 represents a hydrogen atom, a hydroxyl group protecting group, an alkyl, alkenyl, alkynyl or cycloalkyl group having at most 6 carbon atoms, these radicals being optionally substituted, or R1 represents an acyl radical, R2 and R3 are such that: either R2 represents a hydrogen atom and R3 represents a hydrogen atom or an alkyl radical having 1 at 4 carbon atoms, or R3 represents a hydrogen atom and R2 represents: - either a halogen atom, - or an alkyl, cycloalkyl, alkoxy or alkylthio radical having at most 5 carbon atoms, - or a radical acetoxymethyl or carbamoyloxy methyl, or an -NH-1-Alk radical in which Alk is an alkyl having 1 to 4 carbon atoms, or a -CH 2 -S-R 5 radical in which R 5 represents a 5-membered heterocyclic ring; or 6 rings having from 1 to 4 heteroatoms selected from S, N and O and optionally substituted or R5 represents an acyl radical having 2 to 4 carbon atoms or R5 represents a fused heterocycle, - or an azidomethyl radical, A represents a hydrogen atom 'an equivalent of a metal 24624249   alkali, alkaline earth metal, magnesium, ammonium or an organic amine base or an ester group, n represents an integer from 0 to 2p characterized in that it is first treated in a solvent, and optionally in the presence of a base, a product of formula II: R - C02A1 II   In which R and R 1 have the above meaning and A represents a hydrogen atom or an equivalent of alkali metal, alkaline earth metal, magnesium ammonium or an organic amine base, with a product of formula III : R4 S02Ha1 III   wherein R4 represents an alkyl, aryl or aral radical;   optionally substituted alkyl and Hal represents a halogen atom and causes the resulting product to react in a solvent and optionally in the presence of a base on a product of formula IV: (O) t n H2 S. -R3   R2 C02A 2. Process according to claim 1 for the preparation of the products of formula I: - $ A (O) nI CONH IA sO <H2-R0R, CO2H syn isomer   wherein R 'represents a hydrogen atom or a group   protecting the amino group, Rl1 represents a group   protecting the hydroxyl group or an alkyl radical, 2462439   alkenyl or alkynyl having not more than 4 carbon atoms,   R'2 represents an acetoxy, 1-methyl-1 (H) -tetrazol-   -ylthio, 2-methyl-1,3,4-thiadiazolylthio or azido, nt represents 0 or 1 corresponding to a product of formula I in which R represents a 2-amino-1,3-thiazol-4-yl or 2-amino radical. protected 1,3-thiazol-4-yl amino, R1 has the values of Rt1] A represents a hydrogen atom, R2 represents -CH2-Rt2 in which R'2 has the previous values and na the values of n ' characterized in that a product of formula IIA is first treated in a solvent and optionally in the presence of a base: NHR 'ss 2A1 IIA   In which R 'and Rt'1 have the above meaning and A1 represents a hydrogen atom or an equivalent of alkali metal, alkaline earth metal, magnesium, ammonium or an organic amine base, by the tosyl chloride and causes the resulting product to act in a solvent and in the presence of a base on a product of formula IVA: H2N S IVa   N CH -R ' 2- 2 C02H   in which R'2 and nt 'have the preceding meaning.   3. Method according to claims 1 or 2, characterized in that   that the solvent in which the product of formula III is reacted with the product of formula II or tosyl chloride on the product of formula IIA is chosen from the group formed by acetone, dimethylacetamide and acetate;   of ethyl, tetrahydrofuran, acetonitrile, tetra- 2462439   carbon chloride, methylene chloride, toluene, dioxane, isopropyl ether, N-methyl pyrrolidone and dimethylformamide.   4. Process according to claims 1 to 3, characterized in that   that the solvent in which the product of formula III is reacted on product II or tosyl chloride on the product   of formula IIA is dimethylacetamide.   5. Process according to claims 1 to 4, characterized in that   the solvent in which the product resulting from the reaction of the product of formula III with the product of formula II or the product resulting from the action of tosyl chloride is reacted with the product of formula IV or IVa, sure   the product of formula IIA is methylene chloride.   6. Process according to claims 1 to 5, characterized in that   that the base in the presence of which one operates possibly at the   During the different phases of the process is triethylamine.   7. Process according to claims 1 to 6, characterized in that   that the action of the product of formula III on the product of formula II or the action of tosyl chloride on the product of formula IIA as well as the action of the products resulting from these   operations on formula IV or IVa products are carried out killed at low temperature.   8. Process according to Claims 1 to 7 for the preparation of   3-acetoxymethyl 7- [2- (2-amino-4-thiazolyl) -2-methoxy-imino-acetamido] -phi-3-th-4-carboxylic acid isomer, characterized in that the reaction is carried out at low temperature, in dimethylacetamide and in the presence of triethylamine,   tosyl chloride on 2- (2-amino-4-thiazolyl) -2-   isomeric methoxyimino acetic acid and acts in methylene chloride and in the presence of triethylamine the product   resulting on 7-amino cephalosporanic acid.   9. Process according to claims 1 to 7, for the preparation of   3-acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamidofphi-3-th -4-carboxylic acid isomer thereof, characterized in that the reaction is carried out at low temperature in dimethylacetamide; and in the presence of triethylamine, tosyl chloride on 2- (2-tritylamino-4-thiazolyl) acid   2-methoxyimino acetic isomer syn and made act in the chlorine 27 2462439   methylene chloride and in the presence of triethylamine   resulting on 7-amino cephalosporanic acid.